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SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells

Abstract

Colorectal and hepatocellular carcinomas are some of the leading causes of cancer deaths worldwide, but the mechanisms that underly these malignancies are not fully understood. Here we report the identification of SMYD3, a gene that is over-expressed in the majority of colorectal carcinomas and hepatocellular carcinomas. Introduction of SMYD3 into NIH3T3 cells enhanced cell growth, whereas genetic knockdown with small-interfering RNAs (siRNAs) in cancer cells resulted in significant growth suppression. SMYD3 formed a complex with RNA polymerase II through an interaction with the RNA helicase HELZ and transactivated a set of genes that included oncogenes, homeobox genes and genes associated with cell-cycle regulation. SMYD3 bound to a motif, 5′-CCCTCC-3′, present in the promoter region of downstream genes such as Nkx2.8. The SET domain of SMYD3 showed histone H3-lysine 4 (H3-K4)-specific methyltransferase activity, which was enhanced in the presence of the heat-shock protein HSP90A. Our findings suggest that SMYD3 has histone methyltransferase activity and plays an important role in transcriptional regulation as a member of an RNA polymerase complex. Furthermore, activation of SMYD3 may be a key factor in human carcinogenesis.

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Figure 1: Expression of SMYD3 and its subcellular localization.
Figure 2: Effect of SMYD3 on proliferation.
Figure 3: Association of SMYD3 with HELZ, RNA polymerase II and HSP90 in vivo.
Figure 4: Histone methyltransferase activity of SMYD3.
Figure 5: Identification of a SMYD3-binding element in the 5′ flanking region of Nkx2.8.
Figure 6: Transcriptional activation of Nkx2.8 by SMYD3.

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Acknowledgements

We are grateful to Y. Yamane-Tanaka for technical assistance. We thank T. Shimokawa, K. Obama, M. Sakai and M. Tsuge for helpful discussions. This work was supported in part by a Research for the Future Program Grant (00L01402) from the Japan Society for the Promotion of Science.

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Correspondence to Yusuke Nakamura.

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Hamamoto, R., Furukawa, Y., Morita, M. et al. SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol 6, 731–740 (2004). https://doi.org/10.1038/ncb1151

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